A protein closely associated with Alzheimer’s disease has been linked to a neuronal pruning process used in normal brain development. The researchers who reported this discovery, in the Feb. 19 issue of Nature, suggest that this early developmental process, when somehow reactivated later in life, represents the long-sought cause of Alzheimer’s. Other researchers are skeptical about this unusual hypothesis; further experiments testing it are under way.

“What we show is that we have a [self-destruction] signaling pathway that operates in the embryo. What is tantalizing and strongly suggested is that it might be hijacked in the disease,” says Marc Tessier-Lavigne, principal investigator on the study, who also oversees drug-discovery efforts at Genentech Inc. in South San Francisco, Calif.

The study originated in basic research on neuronal pruning, a process in which relatively unused neurons and their nerve-fiber connections (axons) wither and degenerate. This pruning occurs during the brain’s growth spurt in the early months of life; in later life, if the brain is injured, an apparently similar self-destruction process can occur in neurons and their axons close to the injured area.

Seeking the molecular triggers of this self-destruction, Tessier-Lavigne and his colleagues eventually focused on a neuronal receptor known as “death receptor 6,” or DR6. They found that when ambient levels of nerve growth factors, which normally help keep neurons healthy, fall below a certain threshold, the bodies and axons of young neurons expressing DR6 start to decay. Concluding that DR6 serves as a switch for the pathway that normally removes unneeded neurons, the researchers looked for the protein that naturally binds to it and activates it.

Among their list of suspects was a large molecule known as amyloid precursor protein (APP), which they found in abundance in the developing neurons that are subject to this DR6-sensitive pruning process. APP has long been seen as a central actor in Alzheimer’s disease. It protrudes from the outer walls of neurons and, when cleaved a certain way, releases the beta-amyloid protein that later forms in clumps in the brains of people with Alzheimer’s. Most of the early-onset forms of Alzheimer’s that run in families have been attributed to genetic mutations that affect APP or its processing into beta-amyloid.

In cell cultures and in mice, Tessier-Lavigne and his colleagues showed that DR6 could indeed be activated by a specific fragment of APP. Known as N-APP, this fragment is separate from the beta-amyloid segment of APP, although both require the same enzyme, beta secretase, to partially cleave them from the larger APP molecule. In other words, one of beta-amyloid’s molecular siblings appears to play a key role in triggering an automated self-destruction process in the brain.

Tessier-Lavigne wonders how this could be mere coincidence. “Wouldn’t it make sense,” he says, for Alzheimer’s disease, if it makes use of APP, “to hijack a normal physiological mechanism that [APP is] involved in?”

Tessier-Lavigne suspects that in the aging brain, bad genes and the aging process itself can lead to a reduction in the levels of growth factors in certain areas [see recent Dana article on BDNF], or the same brain regions lose their ability to sense growth factors, “perhaps through some aging mechanism in the neuron.” This in turn would lead to the cleavage of APP to release N-APP fragments from neuronal surfaces, activating nearby DR6 receptors to initiate the axonal shrinkage and neuronal degeneration of Alzheimer’s.

While he admits that the case for this hypothesis isn’t nearly conclusive, Tessier-Lavigne cites some supporting evidence: In cell culture studies, for example, researchers have shown that injured neurons express more DR6. Also, APP is overexpressed in the brain after head injuries, which have long been known to increase Alzheimer’s risk. Moreover, key enzymes involved in the N-APP/DR6 pruning pathway are also active in the damaged brain areas of people with Alzheimer’s.

Further experiments needed

If Tessier-Lavigne’s “neuronal pruning” hypothesis of Alzheimer’s proves true, it would mean that researchers who focus on the beta-amyloid clumps or neurofibrillary tangles seen in the disease are looking in the wrong place. But mainstream Alzheimer’s researchers aren’t convinced yet.

“I think that the Tessier-Lavigne paper is beautiful and elegant science, but neither I nor anyone in the Alzheimer’s community with whom I have spoken since the paper appeared sees a likely disease connection there,” says Sam Gandy, a neurobiologist and Alzheimer’s researcher at the Mount Sinai School of Medicine. “This [pruning hypothesis] just doesn’t fit with many of the subtleties of Alzheimer’s pathogenesis.”

Karen Duff, an Alzheimer’s researcher and mouse-model developer at Columbia University, says that the Tessier-Lavigne study is “interesting biology, but its relevance to Alzheimer’s disease is not well supported, so it may well be one of those findings that gets a big splash but dies off.”

Bruce Yankner, another noted Alzheimer’s researcher who works at Harvard Medical School, praises the Tessier-Lavigne study for its illumination of the neuronal pruning pathway but adds that “there’s absolutely no data in this paper about this pathway in Alzheimer’s patients or in humans.”

One big reason for skepticism, Yankner notes, is that Tessier-Lavigne’s neuronal pruning process isn’t seen in the most commonly used mouse model for Alzheimer’s. Often called the “APP mouse,” it is genetically engineered to overexpress a mutant form of APP that causes familial Alzheimer’s. Its brain accumulates extensive beta-amyloid deposits as it ages, and this has made it useful in evaluating the effectiveness of anti-amyloid drugs. But one of the most striking features of this model, commonly viewed as a flaw in its fidelity to human disease, is that it does not show the profound axonal withering and neuronal degeneration also seen in the brains of people with Alzheimer’s.

“You would expect, based on this [pruning hypothesis], that a mouse that had a vast overexpression of this cell-death molecule [N-APP] would show a lot of cell death and pruning, but you just don’t see that,” says Yankner.

Tessier-Lavigne responds that the APP mice simply might not be a good model for human Alzheimer’s: “They may be a very good model of amyloid-beta-driven disease, for example, so you can assess the effect of amyloid-beta, but they may not be a good model for what happens when you activate this APP/DR6 pathway.”

He emphasizes that to activate the neuronal pruning process, it isn’t enough just to have overexpression of APP (and thus N-APP); the neurons also have to be primed for self-destruction by being deprived of growth factors or otherwise weakened so that they lose their responsiveness to growth-factor signals. “If the neurons are healthy, we predict that N-APP does not trigger neurodegeneration of the neurons,” he says, suggesting that in APP mice, the neurons that overexpress APP and its fragments might be simply too healthy to succumb to this process.

Tessier-Lavigne and his colleagues are now studying the pruning pathway in adult human neurons. They also plan to find out more about how N-APP and DR6 interact in animal models, including Alzheimer’s mouse models and mice with weakened nerve growth factor systems.

“We’re obviously eager to move along as rapidly as possible,” he says.